Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models.
Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models.
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在新的小鼠模型中，MLL-ENL导致的髓系白血病不需要Tet1。
DOI：
10.1371/journal.pone.0248425
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Nosaka T
中科院分区：
文献类型：
--
作者：
Ono R;Masuya M;Inoue N;Shinmei M;Ishii S;Maegawa Y;Maharjan BD;Katayama N;Nosaka T
TET 1基因编码一种表观遗传修饰分子，参与5-甲基胞嘧啶的去甲基化。在血液系统恶性肿瘤中，经常发现TET 2的功能丧失突变，TET 2是包括TET 1的泰特家族基因之一，而TET 1的突变不是。然而，临床研究发现TET 1在包括急性髓系白血病在内的一些血液系统恶性肿瘤中高表达。事实上，使用常规Tet 1敲除小鼠的小鼠模型的研究表明，Tet 1通过混合谱系白血病（MLL）融合基因或TET 2突变体参与骨髓性白血病发生。同时，另一项研究表明Tet 1在造血干细胞（HSC）中高度表达，并且HSC中Tet 1的缺失增强了潜在的自我更新能力，这可能与髓系白血病发生有关。为了更精确地研究Tet 1在髓系白血病发生中的作用，我们产生了新的条件Tet 1敲除小鼠，通过与我们先前开发的诱导型MLL-ENL转基因小鼠杂交，这些小鼠被用于产生复合突变小鼠。在诱导表达MLL-ENL的HSC或逆转录病毒转导MLL-ENL的造血祖细胞中，Tet 1的条件性消融对体外白血病永生化没有严重影响。此外，在Tet 1条件性切除的复合突变小鼠模型中，由MLL-ENL诱导表达引起的白血病表型也没有受到严重影响，尽管我们发现MLL融合基因的关键靶基因之一Evi 1在肿瘤细胞中的表达在Tet 1切除条件下显著降低。这些结果表明Tet 1在MLL-ENL的髓系白血病发生中是无效的，这表明Tet 1抑制的治疗应用可能需要仔细评估。
The Ten Eleven Translocation 1 (TET1) gene encodes an epigenetic modifying molecule that is involved in demethylation of 5-methylcytosine. In hematological malignancies, loss-of-function mutations of TET2, which is one of the TET family genes including TET1, are frequently found, while the mutations of TET1 are not. However, clinical studies have revealed that TET1 is highly expressed in some cases of the hematological malignancies including acute myeloid leukemia. Indeed, studies by mouse models using conventional Tet1 knockout mice demonstrated that Tet1 is involved in myeloid leukemogenesis by Mixed Lineage Leukemia (MLL) fusion gene or TET2 mutant. Meanwhile, the other study showed that Tet1 is highly expressed in hematopoietic stem cells (HSCs), and that deletion of Tet1 in HSCs enhances potential self-renewal capacity, which is potentially associated with myeloid leukemogenesis. To examine the role of Tet1 in myeloid leukemogenesis more precisely, we generated novel conditional Tet1-knockout mice, which were used to generate the compound mutant mice by crossing with the inducible MLL-ENL transgenic mice that we developed previously. The leukemic immortalization in vitro was not critically affected by conditional ablation of Tet1 in HSCs with the induced expression of MLL-ENL or in hematopoietic progenitor cells retrovirally transduced with MLL-ENL. In addition, the leukemic phenotypes caused by the induced expression of MLL-ENL in vivo was not also critically affected in the compound mutant mouse model by conditional ablation of Tet1, although we found that the expression of Evi1, which is one of critical target genes of MLL fusion gene, in tumor cells was remarkably low under Tet1-ablated condition. These results revealed that Tet1 was dispensable for the myeloid leukemogenesis by MLL-ENL, suggesting that the therapeutic application of Tet1 inhibition may need careful assessment.
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影响因子：
23.9
作者：
Somervaille TC;Matheny CJ;Spencer GJ;Iwasaki M;Rinn JL;Witten DM;Chang HY;Shurtleff SA;Downing JR;Cleary ML
通讯作者：
Cleary ML
影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
30.5
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
通讯作者：
Aifantis I
影响因子：
5.3
作者：
Ono, R;Ihara, M;Nosaka, T
通讯作者：
Nosaka, T
影响因子：
4.6
作者：
Kunimoto, Hiroyoshi;Fukuchi, Yumi;Sakurai, Masatoshi;Sadahira, Ken;Ikeda, Yasuo;Okamoto, Shinichiro;Nakajima, Hideaki
通讯作者：
Nakajima, Hideaki